Methylation and expression analyses of the 7q autism susceptibility locus genes MEST , COPG2, and TSGA14 in human and anthropoid primate cortices.
ABSTRACT The autism susceptibility locus on human chromosome 7q32 contains the maternally imprinted MEST and the non-imprinted COPG2 and TSGA14 genes. Autism is a disorder of the 'social brain' that has been proposed to be due to an overbalance of paternally expressed genes. To study regulation of the 7q32 locus during anthropoid primate evolution, we analyzed the methylation and expression patterns of MEST, COPG2, and TSGA14 in human, chimpanzee, Old World monkey (baboon and rhesus macaque), and New World monkey (marmoset) cortices. In all human and anthropoid primate cortices, the MEST promoter was hemimethylated, as expected for a differentially methylated imprinting control region, whereas the COPG2 and TSGA14 promoters were completely demethylated, typical for transcriptionally active non-imprinted genes. The MEST gene also showed comparable mRNA expression levels in all analyzed species. In contrast, COPG2 expression was downregulated in the human cortex compared to chimpanzee, Old and New World monkeys. TSGA14 either showed no differential regulation in the human brain compared to chimpanzee and marmoset or a slight upregulation compared to baboon. The human-specific downregulation supports a role for COPG2 in the development of a 'social brain'. Promoter methylation patterns appear to be more stable during evolution than gene expression patterns, suggesting that other mechanisms may be more important for inter-primate differences in gene expression.
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ABSTRACT: Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.EMBO Molecular Medicine 04/2014; · 7.80 Impact Factor
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ABSTRACT: Genomic imprinting is an epigenetically-driven phenomenon that responds to environmental stimuli to determine the fetal growth trajectory. This review aims at describing the transgenerational meaning of genomic imprinting while supporting the study of genomic imprinting in placenta for the determination of an important biomarker of chronic and developmental disorders in children as driven by the environment. Recent work has shown that genomic imprinting reaches beyond the basic significance of an epigenetic mark regulating gene expression. Genomic imprinting has been theorized as the main determinant of epigenetic inheritance. Concomitantly, new studies in the field of molecular epidemiology became available that tie the fetal growth trajectory to genomic imprinting in response to environmental stimuli, making of genomic imprinting the driving force of the fetal growth. When carried out in placenta, the effector of the intrauterine environment as conveyed by the maternal exposure to the general life environment, the study of genomic imprinting may reveal critical information on alterations of the fetal growth trajectory. The study of genomic imprinting profiles in placentas from birth cohorts of individuals exposed to different environmental stimuli can provide a new, much needed, tool for the elaboration of effective public health intervention plans for child health.Current opinion in pediatrics 02/2014; · 2.01 Impact Factor
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ABSTRACT: Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in-silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca(2+) signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.Neurochemistry International 01/2014; · 2.66 Impact Factor